1,3-disubstituted-delta**2-1,2,4-triazolin-5-one-4-acetic acids



United States Patent ice 3,499,000 1,3-DISUBSTITUTED-A -1,2,4-TRIAZ0LlN-5- 0NE-4-ACETIC ACIDS 7 Andre L. Langis, Montreal, Quebec, Canada, assignor to American Home Products Corporation, New York, N.Y., a corporation of Delaware No Drawing. Filed Aug; 4, 1967, Ser. No. 658,326 Int. Cl. C07d 55/06; A61k 27/00 U.S. Cl. 260-308 9 Claims ABSTRACT OF THE DISCLOSURE The presentinvention relates to new 1,3-disubstituted- A -1,2,4-triazolin-S-onel-acetic acids as well as to novel intermediates used in their preparation.

The compounds of this invention possess anti-infiammatory activities when administered locally or orally, and are useful in the treatment of inflammatory conditions. For local administration they may be formulated in the form of solutions, creams, or'lotions, containing 0.5-5.0 percent of the active ingredient and may be applied 10- cally to the inflamed area several times a day. For oral administration, they may be formulated with excipients such as, starch, lactose, magnesium stearate or magnesium silicate in dosage forms such as tablets, or capsules containing from 25 to 250 mg. each of the active ingredient.

More specifically, the compounds of this invention may be represented by Formula I:

acids (I., R =H).

3,499,000 Patented Mar. 3, 1970 acetic acid lower alkyl ester, such as, for example, 3- aroylor 3-aralkyl-4-carbethoxymethyl-1-phenyl-A -1,2, 4-triaZolin-5-one (I R =lower alkyl). Hydrolysis of those last-named esters yields the corresponding 3-arylor 3-aralkyl-1-phenyl-M-1,2,4-triazolin-5-one 4 -'acetic The following examples and formulae in which X, R and R have the significance defined above Will illustrate this invention. The composition of compounds is confirmed by elemental analysis.

(III) EXAMPLE 1 1,3-diphenyl-A -1,2,4-triazolin-5-one Benzoyl urea (13.3 g., 0.075 mole) and phenyl hydrazine (8.1 g., 0.075 mole) are immersed into an oil bath at 155C. The temperature is raised to 175 C. over /2 hour and held there for 5 hours. The solid is filtered and washed with ether to give the crude title compound sents hydrogen or a lower alkyl group such as the methyl,

ethyl or propyl group.

The compounds of this invention may be conveniently prepared by reacting an aroyl or an aralkoyl halide, preferably the chloride of the formula RCOCl in which R has the significance defined above with urea to obtain the intermediate aroyl or aralkoyl urea of the formula RCONHCONH (II) in which R has the significance defined above. Examples of such substituted ureas are benzoyl urea, p-chlorobenzoyl urea, naphthoyl urea, or diphenylacetyl urea. The latter substituted urea of Formula II is then reacted with phenyl hydrazine to obtain the corresponding B-substituted-1-phenyl-A -1,2,4- triazolin-S-one of Formula III. The latter compound is then reacted with a lower alkyl haloacetate of the formula XCH COOR in which X represents a halogen with a molecular weight greater than 19 and R is as defined above, such as, for example, ethyl chloroacetate in the presence of an alkali metal lower alkoxide such as, for example, sodium methoxide to obtain the corresponding 3-arylor 3-aralkyl-1phenyl-A -1,2,4-triazolin-5-one-4- with M.P. 213219 C. Three recrystallizations from alcohol raise the melting point to 233-234 C.

EXAMPLE 2 4-carbethoxymethyl-1,B-diphenyI-A -1,2,4-triazolin-5-one To a solution of 11.85 g. (0.05 mole) of 1,3-diphenyl-1,2,4-triazolin-5-one in ml. of methanol are added 2.7 g. of sodium methoxide. The reaction mixture is stirred and refluxed for 2.5 hours. 9.1 g. of ethyl bromoacetate are added dropwise and the mixture is heated to reflux for 18 hours. After filtration, the solvent is evaporated under reduced pressure. The title compound is obtained as an oil,

vfgf 1752, 1710, 1375 and may be used without further purification for the sub sequent hydrolysis.

EXAMPLE 3 1,3-diphenyl-A -1,2,4-triazolin-5 one-4Eacetic acid 1,3-diphenyl-4-carbethoxymethyl-A -1,2,4-triazolin 5 one (2.0 g.) is dissolved in 20 ml. of formic acid and 1.0 g. of methane sulfuric acid is added to the solution. After heating to reflux for 5 hours, the solution is evaporatedyto dryness under reduced pressure. The product is dissolved in chloroform and the solution is Washed with water, dried over sodium sulfate and the solvent evaporated. The title compound is obtained with M.P. 196- 198 C. after crystallization from ethanol.

EXAMPLE 4 3-(4'-chlorophenyl)-1-phenyI-A -1,2,4-traizolin-5-one p-Chlorobenzoyl urea (15.4 g., 0.0825 mole) and 8.9 g. (0.0825 mole) phenylhydrazine in ml. Decalin are heated to refiux for 12 hours. A solid separates on cooling. It is collected and recrystallized from nitromethane: methanolzchloroform to give the title compound with M.P. 284-286 C. after sublimation at 250-255 C. and 0.51 mm. Hg pressure.

3 EXAMPLE 4-carbethoxymethyl-3-(4-chlorophenyl)-1-phcnyl- A -1,2,4-triazolin-5-one To a solution of 67.6 g. (0.248 mole) of l-phenyl- 3-(4'-chlorophenyl)-A -1,2,4-triazolin-5-one in 750 ml. of dry methanol there are added 13.4 g. of sodium methoxide, and the mixture is heated to reflux for 2.5 hours. Ethyl brornoacetate (45.1 g.) is added dropwise to the mixture which is refluxed for 9 hours. The inorganic salts are collected and the filtrate is evaporated to dryness under reduced pressure. The product. is dissolved in chloroform and the solution is washed with water (2X25 cc.) and dried over sodium sulfate. The solvent is evaporated to yield the title compound with M.P. 122-123 C. after crystallization from ethanol.

EXAMPLE 6 3- 4-p-chlorophenyl) 1-pheny1-A -1,2,4-triazolin-5- one-4-acetic acid A solution of 9.0 g. of 4-carbethoxymethyl-3,(4-chlorophenyl)-1-phenyl-A -1,2,4-triazolin-5-one in a mixture of 100 ml. of formic acid and 5 ml. of methane sulfonic acid is heated to reflux for 7 hours and then cooled. The crystals are collected and recrystallized from ethanol to give the title compound with M.P. 190192 C.

EXAMPLE. 7

3-(1'-naphthyl)-1-pheny1-A -l,2,4-triazolin-5-one l-naphthyloylurea (26.8 g., 0.125 mole) and 13.5 g. (0.125 mole) of phenylhydrazine in 175 ml. of Decalin are heated to reflux for 8 hours. The crystals separating upon cooling are collected and washed with ether. The product is recrystallized from a mixture of nitromethane, methanol and chloroform to yield the title com-pound with M.P. 257260 C.

EXAMPLE 8 4- ca rb ethoxymethyl-3 1 -naphthyl)-1-phenyl- A 1,2,4-triazolin-5-one To a solution of 12.75 g. of 3-(1'-naphthyl-1-phenyl- A -1,2,4-triazolin-5-one in 100 ml. of dry methanol are added 2.4 g. sodium methylate. The reaction mixture is stirred and refluxed for 2.5 hours. Ethyl bromoacetate (8.05 g.) is added dropwise and the mixture is stirred and refluxed for 9 hours. The inorganic salts are collected and the filtrate is evaporated to dryness under reduced pressure. The product is dissolved in chloroform. The solution-is washed with Water, dried over sodium sulfate, and the solvent evaporated. The residue is recrystallized from ethanol to yield the title compound with M.P. IDS-106 C.

EXAMPLE 9 3-(1-naphthyl)-1-pheny1-A -1,2,4-triazolin-5-one-4- acetic acid A solution of 9.0 g. of 4-carbethoxymethy1-3-(1'-naphthyl)-1-phenyl-A -1,2,4-triazolin-5-one in a mixture of 100 ml. of formic acid and 5 m1. of methanesulfonic acid is heated to reflux for 7 hours. It is then evaporated to dryness under reduced pressure. The product is recrystallized from a mixture of acetone and hexane to give the title compound with M.P. 190192 C.

EXAMPLE 10 3-benzhydryl-1-pheny1-A -1,2,4-triazolin-5-one Diphenylacetyl urea (14.9 g., 0.058 mole) and (6.33 g., 0.058 mole) of phenylhydrazine in 95 ml. of Decalin are heated to reflux for 8 hours. The crystals are collected and Washed with ether. The product is recrystallized fom methanol to give the title compound with M.P. 204-208 C.

EXAMPLE 11 3-benzhydry1-4-carbethoxymethyl-1-pheny1-A -1,2,4-

triazolin-S-one To a solution of 71.0 g. (0.21 mole) of 3-benzhydryl- 1-phenyl-A -1,2,4-triazolin-5-one in 1,000 ml. of methanol are added 11.7 g. of sodium methoxide. The reaction mixture is stirred and refluxed for 2.5 hours. Ethyl bromoacetate (36.2 g.) is added dropwise and the mixture is heated to reflux for 18 hours. After cooling, the crystals are collected and recrystallized from ethanol to give the title compound with M.P. 182184 C.

EXAMPLE l2 3benzhydryl-1-pheny1-A -1,2,4-triazo1in-5-one- 4-acetic acid A solution of 8.3 g. (0.02 mole) of 3-benzhydryl-4- carbethoxymethyl-l-phenyl-n -1,2,4-triazolin-5-one in a mixture of ml. of formic acid and 5 ml. of methanesulfonic acid is heated to reflux for 10 hours. It is evaporated to drynes under reduced presure. The residue is dissolved in chloroform and the solution washed with water (3X 15 cc.). The chloroform solution is dried over sodium sulfate and evaporated under reduced pressure. The residue is recrystallized from a hexane-methanol mixture to give the title compound with M.P. 194l96 C.

I claim:

1. A compound of the formula ll N 0:0

wherein R is selected from the group which consists of phenyl, p-chlorophenyl, naphthyl and diphenylmethyl; and R is selected from the group which consists of hydrogen and lower alkyl.

2. 1,3-diphenyl-A -1,2,4-triazolin-5-one-4-acetic acid, as claimed in claim 1.

3. 3 (4' chlorophenyl)-1-phenylA -1,2,4-triazolin- 5-one-4-acetic acid, as claimed in claim 1.

4. 3-(1'-naphthyl)-1-phenyl-A -l,2,4-triazolin 5 one- 4-acetic acid, as claimed in claim 1.

5. 3-benzhydryl-1-phenyl-A -1,2,4 triazolin 5 one- 4-acetic acid, as claimed in claim 1.

6. 4-carbethoxymethyl-1,3-diphenyl-A -1,2,4 triazolin- 5-one, as claimed in claim 1.

7. 4 earbethoxymethyl-B-(4-chlorophenyl)-1-phenyl- A -1,2,4-triazolin-5-one, as claimed in claim 1.

8. 4-carbethoxymethyl 3 (1-naphthyl)-1-pheny1-A 1,2,4-triazo1in-5-one, as claimed in claim 1.

9. 3 benzhydryl-4-carbethoxymethyl 1 phenyl-A 1,2,4-triazolin-5-one, as claimed in claim 1.

References Cited FOREIGN PATENTS 971,606 9/1964 Great Britain.

ALTON D. ROLLINS, Primary Examiner US. Cl. X.R. 26055 3; 424269 

